Abstract
Cardiovascular diseases (CVD) remain a major global health challenge. Early markers of disease initiation and progression are urgently needed. We, and others, have previously shown changes in the gut microbiome in association with metabolic and CVD. Here, we demonstrate that gut microbiome-related changes can be detected in association with subclinical variations in heart and kidney function. Markers related to gut microbial metabolism of aromatic amino acids, phenylalanine and tyrosine, associate with circulating pro-atrial natriuretic peptide and estimated glomerular filtration rate in a metabolically healthy European population. Observational and genetic evidence further identify microbiome-related metabolites as mediators of this gut microbiome-kidney axis, with their baseline levels associating with incident CVD in an external Canadian population. Altogether, our work suggests that the gut microbiome interacts with the cardiorenal axis and participates in an interorgan crosstalk affecting host physiology and risk of CVD.
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Data availability
Raw shotgun sequencing data generated in this study have been deposited in the European Nucleotide Archive under accession codes PRJEB41311, PRJEB38742 and PRJEB37249 with public access. The Serum NMR metabolome data generated in this study have been deposited to Metabolights with accession number “MTBLS3429”, and can additionally be requested by contacting the corresponding authors. The Serum GC-MS and isotopically quantified serum metabolites (UPLC–MS/MS) data generated in this study have been deposited in MassIVE database with accession numbers “MSV000088042 [https://doi.org/10.25345/C5CV76]” and “MSV000088043 [https://doi.org/10.25345/C58246]”, respectively. In adherence to EU and national privacy laws, unrestricted access to individual phenotypic data cannot be provided for the MetaCardis study. Interested researchers, wishing to access individual phenotypic data would need to submit argued applications to the relevant National Data Protection Agencies. These are the Danish Data Protection Agency (https://www.datatilsynet.dk/english) for phenotypic data from study participants recruited in Denmark, the Federal Commissioner for Data Protection (https://www.bfdi.bund.de/EN/Home/home_node.html) for phenotypic data from study participants recruited in Germany and the Commission Nationale Informatique & Libertés (https://www.cnil.fr/en/home) for phenotypic data of study participants recruited in France. Application procedures are given on the outlined websites. If such permission is granted, phenotypic data will be then made available by the corresponding authors within 5 weeks. All omics and phenotypic data from the Canadian Longitudinal Study on Aging (www.clsa-elcv.ca) are protected by Canadian personal data privacy laws. The CLSA data are only available to researchers who meet the criteria for access to de-identified CLSA data. Source data are provided with this paper.
Code availability
No custom code or algorithm was used for the analyses conducted in this work.
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Acknowledgements
This study was initiated and funded by the European Community’s Seventh Framework Programme (FP7/2007-2013): MetaCardis, grant agreement HEALTH-F4-2012-305312, a Joint Programming Initiative (A healthy diet for a healthy life; 2017-01996_3), a Transatlantic Networks of Excellence Award from the Leducq Foundation (17CVD01) and by the NIHR Imperial Biomedical Research Centre. GC-MS analysis in EGEA was funded by a grant from the Agence Nationale pour la Recherche (METABASTHMA, ANR-17-CE14-0042-01). Genotyping in EGEA was supported by grants from the European Commission (No. LSHB-CT-2006-018996-GABRIEL) and the Wellcome Trust (WT084703MA). We thank the EGEA study participants, and Hamida Mohamdi and Patricia Margaritte-Jeannin for their contribution to this work. This work was also supported by the Agence Nationale de la Recherche (ANR) with the MetaGenoPolis grant (ANR-11-DPBS-0001). Infrastructure support for this research was provided by the NIHR Imperial BRC. This research is also funded by grants from the French National Research Agency (ANR-10-LABX-46 [European Genomics Institute for Diabetes]), from the National Centre for Precision Diabetic Medicine – PreciDIAB, which is jointly supported by the French National Agency for Research (ANR-18-IBHU-0001), by the European Union (FEDER), by the Hauts-de-France Regional Council (Agreement 20001891/NP0025517), by the European Metropolis of Lille (MEL, Agreement 2019_ESR_11) and by Isite ULNE (R-002-20-TALENT-DUMAS), also jointly funded by ANR (ANR-16-IDEX-0004-ULNE), the Hauts-de-France Regional Council (20002845) and by the European Metropolis of Lille (MEL) and ERC Generator Grant “Richness” (R-ERCGEN-23-003-DUMAS) from the University of Lille. This research was also conducted as part of the CNRS–Imperial-ULille International Research Project in Integrative Metabolism “METABO-LIC”. The authors also acknowledge that this research was made possible using the data/biospecimens collected by the Canadian Longitudinal Study on Aging (CLSA). Funding for CLSA is provided by the Government of Canada through the Canadian Institutes of Health Research (CIHR) under grant reference: LSA 94473 and the Canada Foundation for Innovation, as well as the following provinces, Newfoundland, Nova Scotia, Quebec, Ontario, Manitoba, Alberta, and British Columbia. This research has been conducted using the CLSA metabolomics data version 1, CLSA Comprehensive baseline dataset (v7), Comprehensive follow-up 1 dataset (v5), CLSA participant status data under Application Number 2104039. The CLSA is led by Drs. Parminder Raina, Christina Wolfson and Susan Kirkland. K.Che. is supported by the NIHR Imperial Biomedical Research Centre (BRC) through a fellowship jointly funded by the Cardiovascular and Multimorbidity Themes. K.Che also acknowledges the support of the Medical Research Council Skills Development Fellowship (grant no. MR/S020039/1) and the Wellcome Trust-funded Institutional Strategic Support Springboard Fellowship (grant no. 204834/Z/16/Z). R.C. is the recipient of the Walter Benjamin Fellowship from the German Research Association (DFG) project number 462524713 and the EASO-Novo Nordisk Foundation New Investigator Award: Clinical Research, project number NNF25SA010378. L.H. was a recipient of an MRC Intermediate Research Fellowship in Data Science (grant number MR/L01632X/1, UK Med-Bio) and is supported by the European Union’s Horizon 2020 research and innovation programme (grant agreement number 874583). A.R.M. was recipient of a Doctoral Training Centre PhD scholarship (MR/K501281/1), Imperial College PhD-scholarship (EP/M506345/1) and a La Caixa studentship. A.L.N. received a Portuguese Foundation for Science and Technology (SFRH/BD/52036/2012) scholarship. F.M. and D.G. are recipients of the INSERM International Research Project DIABETOMARKERS. P.A. is the recipient of a Career Development Award from the Medical Research Council (Grant No. MR/Y010051/1). V.Z. acknowledges funding support from the United Kingdom Research and Innovation Medical Research Council grant MR/W029790/1 and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK MRC, Alzheimer’s Society and Alzheimer’s Research UK. I.T. acknowledges support from the Imperial College British Heart Foundation Centre for Research Excellence (RE/24/130023) and the NIHR Imperial Biomedical Research Centre. S.K.F. acknowledges funding support from EU: IMMEDIATE consortium, DFG: SFB1470, TRR412 and EXC3118 (ImmunoPreCept), and from DZHK (German Centre for Cardiovascular Research). M.S. acknowledges grant support from the Deutsche Forschungsgemeinschaft (DFG), EXC3105-1. K.Cle. also acknowledges support from the CNIEL (Centre National Interprofessional de l’Economie Laitiere) and BNP-Cardiff for grant support on nutritional aspects in this cohort, the Inserm (IRP programme), the ANR (NutrimCheck project) and Horizon Europe, European Commission EIC Pathfinder “Nutrimune”, European community. M.-E.D. acknowledges funding support from the EU IMMEDIATE consortium under contract number 101095540 and UKRI Innovate UK under contract number 101095556 and by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, as well as grants from Guts UK (DG201808), Diabetes UK (19/0006059), and a Medical Research Council grant to M.-E.D. and P.F. (MR/X010155/1). The Novo Nordisk Foundation Centre for Basic Metabolic Research is an independent research institution at Faculty of Health and Medical Sciences, the University of Copenhagen, partially funded by an unrestricted donation from the Novo Nordisk Foundation (NNF23SA0084103). The opinions expressed in this manuscript are the author’s own and do not reflect the views of the Canadian Longitudinal Study on Aging. Also, despite being funded by the European Union, views and opinions expressed are those of the author(s) only and do not necessarily reflect those of the European Union or European Health and Digital Executive Agency (HADEA). Neither the European Union nor the granting authority can be held responsible for them.
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K.Che., M.-E.D., K.Cle, S.D.E., and O.P. developed the present study concept and protocol. K.Cle (Coordinator and principal investigator), M.-E.D., S.D.E., O.P., P.B., M.S., J.R., J.B.N., D.G. and F.B. conceived the study design of the MetaCardis consortium. MetaCardis cohort recruitment, phenotyping and lifestyle recording were conducted by J.A.-W., T.N., R.C., C.L., L.K., T.H., T.H.H., H.V., N.B.S., H.K.P., J.N., S.H., M.Blu. MetaCardis consortium data curation was undertaken by R.C., S.A., S.K.F., J.A.-W., and T.N. Faecal microbial DNA extraction and shotgun sequencing N.P., E.L.C., S.F., H.R., B.Q., N.G., M.Ber., P.B.L., K.D.S., P.G., J.D.Z., I.L., J.M.O., P.F. Bacterial cell count measurement: G.F., SVS. Serum and urine metabolome profiling (MetaCardis): L.H., J.C., A.Myr, D.G., F.M. MetaCardis metabolite annotation by J.C., A.Myr, M.O., A.L.N. Pro-ANP measurements by PDM and J.-P.G. Bioinformatics and statistical analyses: K.Che, S.F., S.K.F., B.J., L.P.C., L.M.G., E.P., Ebel, F.P., P.A., F.P.C., R.P.T., I.C.D. GC-MS analysis and GWAS of 4-cresol in EGEA study: E.Bou, F.D., M.L., D.G., K.S., T.A.S. and F.M. CLSA data access and analysis: K.Che, M.J., AMan, P.R., M.L., M.-E.D. Mendelian Randomization: KChe with input from V.Z., A.D., I.T. The manuscript was drafted by KChe and M-ED with inputs from R.C., S.K.F., O.P., K.Cle and S.D.E. All authors approved the final version for publication.
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K.Cle. has held a collaborative research contract with Danone Research in the context of MetaCardis project. O.P. is a co-founder of GutCRINE. F.B. is shareholder of Implexion pharma AB and Roxbiosens, receives research grants from Biogaia AB and Novo Nordisk A/S and is on the scientific advisory board of Bactolife A/S. V.T. is shareholder of Roxbiosens. K.S. and T.A.S. are employees of Shimadzu, Kyoto, Japan. M.Blu. received honoraria as a consultant and speaker from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Lilly, Novo Nordisk, Novartis, and Sanofi. The remaining authors declare no competing interests.
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Chechi, K., Chakaroun, R., Myridakis, A. et al. A gut microbiome-kidney-heart axis predictive of future cardiovascular diseases. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69405-0
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DOI: https://doi.org/10.1038/s41467-026-69405-0
